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Sorting cells through levitation

What looks like a row of drifting gumdrops could hold a wealth of information for both clinical researchers and bench scientists. A team of bioengineers and geneticists has designed a device that can suspend a single living cell between magnets and measure its density based on how high it floats. Such measurements could be used to sort different types of cells—to distinguish cancerous cells from healthy ones, for example—or to measure how cells change when exposed to drugs.

A demonstration of the approach, published online today in the Proceedings of the National Academy of Sciences, is “pretty amazing stuff that could be a game changer for a lot of things if true,” says John Minna, a cancer biologist at the University of Texas Southwestern Medical Center in Dallas.

Researchers have used magnets before to levitate whole creatures, such as living frogs—a bizarre demonstration that won its author an Ig Nobel Prize. “Every material, every cell in nature has a magnetic susceptibility,” explains Utkan Demirci, a bioengineer at Stanford University in Palo Alto, California. But he and his colleagues were looking for new ways to manipulate and assemble tiny pieces of tissue using magnets—a much harder feat, he says, because for an object smaller than about 20 microns, “the magnetic force scales so much down that it couldn’t lift its own gravitational weight.” Another common approach to levitation involves filling an object with iron oxide particles. But that would be toxic to living cells.

To get around that problem, Demirci’s group fiddled not with the magnetic properties of the cells themselves, but with the medium around them. The researchers created a narrow, fluid-filled channel between two long, thin magnets roughly the size of toothpicks. They laced the fluid with particles of gadolinium, a rare-earth metal that is highly magnetic and sometimes given to patients to increase contrast in an MRI. The magnetic field is shaped to pull the gadolinium downward so metal particles push the cells upward, creating a buoyant force just like the one that floats a boat.

That means that the height at which a cell levitates depends on its density. Cells exactly as dense as the gadolinium medium will hover in the middle of the channel, but cells of higher density will sink slightly. By positioning mirrors along the channel that reflect light into a microscope, the researchers could observe the levitating cells in real time.

The researchers then observed that different types of cells levitated at distinctive heights. For example, cancer cells floated above denser blood cells, which could allow clinicians to spot rare circulating tumor cells in a patient sample. The device could also distinguish red blood cells from white blood cells, meaning it could be used to detect low white blood cell counts—a common complication of chemotherapy and a sign that a patient is prone to infection.

Traditional methods for sorting cells rely on fluorescent molecular tags, designed to stick to the surface proteins present on certain types of cells but not on others. Sorting by density is an enticing alternative, says Will Grover, a bioengineer at the University of California, Riverside, who was not involved in the new work. For one, it could be much simpler than designing unique labels. “Density comes for free,” Grover says. “You don’t have to do anything to the cells.”

The technique could also lead to more reliable diagnostic tests. Cancer cells are so diverse that certain ones might not bear the antibody to which a molecular label is supposed to attach. And such errors can lead to false positive and false negative results. The dance of levitating cells can also carry information about how well a drug works. As a cell dies, channels in its porous membrane let in surrounding fluid, increasing its density and causing it to sink to the bottom of the chamber. Researchers could identify which individual cells—from a tumor or a strain of bacteria—survive a drug treatment and study them further, something that's not possible with current culture-and-stain tests, Demirci says.

Levitation is far from the only method for measuring cell density, notes Grover, who has developed a different technique for weighing single living cells by sticking them onto a tiny resonator and measuring changes in its vibration. That approach measures one cell at a time, so the new magnetic platform might have advantages for scaling up the process, Grover says. So far, the setup can get through about 3000 cells per hour. But Grover notes that existing techniques that fluorescently label cells can sort through millions in an hour. Cells can also be crudely sorted en masse with centrifuges. But that technique can’t tell the density of an individual cell or observe real-time density changes.

The researchers are now working to test the limits of their device’s sensitivity and figure out how many strains of cells can be reliably distinguished from one another. They’re also developing a version that attaches to cellphone cameras as a quick and portable diagnostic test.